Process for the hydrolysis of the 3-enamine of 6alpha-methyl-11beta, 21-dihydroxy-4,17(20)-pregnadien-3-one



States r Mich., assignors to. The Upjohn Micl1., a corporationof Dela-Barney J. Magerlein,

Spero, Kalamazoo, Company, Kalamazoo, ware.

No Drawing. Application January 21', 1959 Serial No..788,051

'5 Claims.v (Cl. 260-39145) This invention relates to an improvedprocess for the hydrolysis of certain steroid 3-enamines, to thecorresponding 3'-keto steroids, more particularly to' an improvement inthe alkaline hydrolysis of the 3-pyrrolidyl enamine of6a-rnethyl-11,8,21-dihydroxy-4,17(20) pregnadien-3-one which comprisesconverting theS-enamine to-an acid addition salt thereof prior to thealkaline hydrolysis.

The alkaline hydrolysis of 3-enamines is a known reaction [Hogg et al.,J. Am. Chem. Soc., 77: 4436 (1955)]. However, when this reaction wasapplied to the 3-pyrrolidyl enamine of 6a-methyl-11,8,21-dihydroxy-4,17(-20)*pregnadien-3-one [Spero et al., J. Am. Chem. Soc., 78: 6213(1956)],the yield ofdesired 6u-methyl- 1 1/3,21-dihydroxy-4,17(20)-pregnadien-3-one was considerablydessthan was obtained-when thecorresponding hydrolysis was conducted on the 3-pyrrolidyl enamine of115,21 dihydroxy 4,17(20) pregnadien 3 one. Whereas the hydrolysis ofthe latter compound at room temperature produced satisfactory yields,the hydrolysis of the former compound under the same conditions gaveonly a 20% yield of desired product, calculated on the starting3,11-diketo-6a-methyl-4,17(20)-[cis]-pregnadien- 21-oic acid methylester. Even prolonged heating raised the yield only slightly.

We have now found that when the 3-pyrrolidyl enamine of 6a methyl 115,21dihydroxy 4,17(20) [cis]- pregnadien 3 one, i.e., 3 pyrrolidyl 6 methyl-11fl,21 dihydroxy 3,5,17(20) [cis] pregnatriene, is converted'to an acidaddition salt thereof prior to the hydrolysis, an over-all yield ofabout 40-50%, calculated from the starting3,11-diketo-6u-methyl-4,17(20)-[cis]- pregnadien-Zl-oic acid methylester, can be achieved even without heating. Whereas the hydrolysisreaction without the acid addition salt step required chromatographicseparation in order to isolate the desired product, the process of thisinvention gave more than twice the amount of product by directcrystallization, an advantage of particular significance in commercialproduction. This increase in yield of an intermediate useful in theproduction of the highly active anti-inflammatory agent 6amethyl11fi,17a,21 trihydroxy 4 pregnene 3,20- dione 21-acetate, isparticularly significant in view of the number of steps necessary forits production (Spero et al., supra).

The starting compound in the process of this invention is the3-pyrrolidyl enamine of6a-methyl-11p,21-dihydroxy-4,17(20)-pregnadien-3-one, especially the3-pyrrolidyl enamine of 6a-methyl-11p,21-dihydroxy-4,17(20)-[cisJ-pregnadien-B-one, which is prepared from3,11-diketo-4,l7(20)-pregnadien-21-oic acid methyl ester (Spero et al.,supra).

These enamines are converted to an acid addition salt by reaction withan inorganic or organic acid in the usual manner for the production ofamine acid addition salts. However, if aqueous conditions are employed,it is pre ferred that the solution or suspension containing the acid2,920,085 Patented J an. 5,1 19.60

additiofisalt is madealkaline immediately as the yield-of: desiredproduct is reduced when the 3-enamine ismaimtainedunder aqueous acidicconditions for prolongedperiods; Moreovenbecause of the presence of thelabile 1*1 flehydroxy group, heating under aqueous acidic condi-- tionsshould be avoided.

Acid addition salts which may be employed include both inorganic andorganic acid addition salts, preferably the latter, especiallylower-hydrocarbon carboxylic acid addition salts, i.e., containing from1 to 8 carbon atoms. Representative acidadditionsalts, e.g.,.preparedfrom thecorresponding 3-enamine and acid, include the hydro-' chloride,hydrobromide, sulfate, phosphate, nitrate, acetate, formate, propionate,butyrate, chloroacetate ben zoate, .trichlorobenzoate, trifiuoroacetate,etc.

The following preparation and example are illustrative offtheprocess ofthis invention, but are not to be construed as limiting.

' PREPARATION 3-pyrrolidyl-6-methyl-11fl21-dihydr0xy-3,5,17(20)[cis]-pregnatriene p A solution of 3.7 g. of6a-rneth'yl-3,11,diketo-4,17(20)-- [cisLpregnadien-Zl-oic acid methylester [Spero et al.,.

I. Am. Chem. Soc., 78: 6213 (1956)], 70 mg. of ptoluene-sulfonic acidand 1.65 ml. of pyrrolidine in 'ml..

of," benzene was refluxed for one hour with the water formed during thereaction being continuously separated? from the refluxing benzene in aDean-Stark trap. The solventwas then removed under vacuum. The residue,consisting essentially of 3-pyrrolidyl-6-methyl-ll-keto-3,5,17(20)-[cis]-pregnatrien-Zl-oic acid methyl ester, was dissolved in50 ml. of anhydrous ether and then added to a suspension of 1.2 g. oflithium aluminum hydride in ml. of ether. After heating under reflux forone hour, the reaction mixture was cooled and then 7.5 ml. of ethylacetate was cautiously added followed by 18 ml. of water to precipitatethe inorganic salts as a thick paste. The ether phase contained thedissolved 3-pyrrolidyl 6 methyl 115,21 dihydroxy 3,5,17(20)-[cis]-pregnatriene.

The corresponding trans isomer is prepared by starting with methyl3,11-diketo-4,17(20)-[trans]-pregnadien-21- oic acid methyl ester which,in turn, is prepared by refluxing a methanolic solution of thecorresponding cis isomer in the presence of sodium methoxide.

EXAMPLE 6ot-methyl-11fi,21-dihydroxy-4,17(20)-[cis]- pregnadien-3-one A.OLD METHOD The total reaction mixture obtained as described in thepreparation and containing the 3-pyrrolidyl-6-methyl- 115,21 dihydroxy3,5,17(20) [cis] pregnatriene was distilled to dryness under vacuum andthe residue covered with nitrogen and to it was then added ml. ofmethanol. After stirring at 25 C. for 5 minutes, 10 ml. of 5% sodiumhydroxide was added. The reaction mixture was stirred at 25 C. for 1.5hours. The pH of the mixture was adjusted to 7 with 3 ml. of acetic acidand the solvent distilled under vacuum. A solution of 12.5 ml. ofconcentrated hydrochloric acid in 200 ml. of water was added. Theproduct was extracted from the resulting mixture with methylenechloride. The solution was dried and the methylene chloride distilled.The 3 g. residue was dissolved in ethyl acetate and seeded, but crystalsfailed to form so the solution was evaporated to dryness, redissolved in400 ml. of methylene chloride and chromatographed over 240 g. ofmagnesium silicate (Florisil). The column was developed with hexanes(Skellysolve B) containing increasing proportions of ace tone. 1.03 g.of 11p,2l-dihydroxy-4,17(20)-[cisl-pregnadien-3-one was eluted withhexanes plus 20% acetone and hexanes plus 30% acetone. No significantamount of this compound was present in any of the other eluatefractions. Purification of this compound by crystallization from ethylacetate gave 0.7 g., a yield of 20% of the theoretical, calculated fromthe starting 3,11-diketo-6amethyl-4,17(20)-[cis]-pregnadien-21-oic acidmethyl ester, of crystals melting at 172-174" C., having an [411 of +125(CI-ICI anda Mir. of aM 15,200 13,. NEW METHOD The ether layer obtainedas described in the prepara tion and containing the3-pyn'olidyl-6-methyl-l15,21-dihydroxy-3,5,l7(20)-[cisJ-pregnatriene wasdecanted from the precipitated inorganic salts and the salts thenextracted with two 25-ml. portions of ether. The ether phase and etherextracts were combined and then mixed with a solution of 3 ml. of aceticacid in 15 ml. of methanol, thereby producing the minimum acid additionsalt. 37 ml. of 10% aqueous sodium hydroxide was immediately added tothe acidic mixture which was then stirred for minutes. 40 ml. of waterwas added and the ether layer separated. The aqueous layer was extractedwith 40 ml. of ether and the ether extract and ether layer combined andthen washed successively with dilute hydrochloric acid, water, aqueoussodium bicarbonate and then saturated aqueous sodium chloride solution.The ether was dried over sodium sulfate and then distilled leaving a 3.2g. residue of 11fl,21-dihydroxy-4,17(20)- [cisl-pregnadien-B-one.Purification of this compound by crystallization from ethyl acetate gave1.5 g., a yield of 44% of the theoretical calculated from the starting v4 3,11 diketo methyl 4,17 (20) [cis] pregnadien- 21-oic acid methylester, of crystals melting at 172-174 C., having an [oil of (CHCI and 2.

Min. f 242, aM 14,850

Following the above procedure, comparable results are obtained bysubstituting an equivalent amount of methanolic hydrogen chloride forthe acetic acid or the correspondingtrans isomer as starting compound.

We claim:

1. In a process for the hydrolysis of the 3-pyrrolidyl enamine of6a-rnethyl-1 1 18,2 1-dihydroxy-4, l 7 20) -pregnadien-S-one underalkaline conditions to produce6amethyl-11,3,21-dihydroxy-4,17(20)-pregnadien-3-one, the improvementwhich comprises converting the 3-enamine to an acid addition saltthereof prior to the alkaline hydrolysis.

2. The process of claim 1, wherein the acid addition salt is an organicacid addition salt.

3. The process of claim 1, wherein the acid addition.

salt is a lower-hydrocarbon carboxylic acid addition salt.

4. The process of claim 1, wherein the acid addition salt is theacetate.

5. The process of claim 1, wherein the starting compound is3-pyrrolidyl-6-methyl-11p,21-dihydroxy-3,5,17- (20)-[cis]-pregnatrieneand the acid addition salt is the acetate.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No,2,920,085

Barney J, Magerlein et a1,

It is hereby certified that error appears in the-printed specificationof the above numbered patent requiring correction and that the saidLetters Patent should read as corrected below.

101cm 3, line for "minimum" read m iminium no Signed and sealed this7th. day of June 1960.

(SEAL) Attest:

KARL H AXLINE ROBERT C. WATSON Commissioner of Patents Attesting Officer

1. IN A PROCESS FOR THE HYDROLYSIS OF THE 3-PYRROLIDYL ENAMINE OF6A-METHYL-11B,21-DIHYDROXY-4,17(20)-PREGNADIEN-3-ONE UNDER ALKALINECONDITIONS TO PRODUCE6AMETHYL-11B,21-DIHYDROXY-4,17(20)-PREGNADIEN-3-3-ONE, THE IMPROVEMENTWHICH COMPRISES CONVERTING THE 3-ENAMINE TO AN ACID ADDITION SALTTHEREOF PRIOR TO THE ALKALINE HYDROLYSIS.